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Activated astrocytes play a pathological role in X\u2010ALD. Recently, reactive astrocytes have been shown to induce neuronal cell death via saturated lipids in high\u2010density lipoprotein (HDL), although how HDL from reactive astrocytes exhibits neurotoxic effects has yet to be determined. In this study, we obtained astrocytes from wild\u2010type and <jats:italic>Abcd1<\/jats:italic>\u2010deficient mice. HDL was purified from the culture supernatant of astrocytes, and the effect of HDL on neurons was evaluated in vitro. To our knowledge, this study shows for the first time that HDL obtained from <jats:italic>Abcd1\u2010<\/jats:italic>deficient reactive astrocytes induces a significantly higher level of lactate dehydrogenase (LDH) release, a marker of cell damage, from mouse primary cortical neurons as compared to HDL from wild\u2010type reactive astrocytes. Notably, HDL from <jats:italic>Abcd1\u2010<\/jats:italic>deficient astrocytes contained significantly high amounts of VLCFA\u2010containing phosphatidylcholine (PC) and LysoPC. Activation of <jats:italic>Abcd1\u2010<\/jats:italic>deficient astrocytes led to the production of HDL containing decreased amounts of PC with arachidonic acid in <jats:italic>sn<\/jats:italic>\u20102 acyl moieties and increased amounts of LysoPC, presumably through cytosolic phospholipase A<jats:sub>2<\/jats:sub>\u03b1 upregulation. These results suggest that compositional changes in PC and LysoPC in HDL, due to <jats:italic>Abcd1<\/jats:italic> deficiency and astrocyte activation, may contribute to neuronal damage. Our findings provide novel insights into central nervous system pathology in X\u2010ALD.<\/jats:p>","DOI":"10.1002\/jimd.12703","type":"journal-article","created":{"date-parts":[[2023,12,26]],"date-time":"2023-12-26T07:08:16Z","timestamp":1703574496000},"page":"289-301","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Increased neurotoxicity of high\u2010density lipoprotein secreted from murine reactive astrocytes deficient in a peroxisomal very\u2010long\u2010chain fatty acid transporter <scp><i>Abcd1<\/i><\/scp>"],"prefix":"10.1002","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4315-0589","authenticated-orcid":false,"given":"Naoki","family":"Fujitani","sequence":"first","affiliation":[{"name":"Sohyaku, Innovative Research Division Research Unit\/Neuroscience, Mitsubishi Tanabe Pharma Corporation  Yokohama\u2010shi Kanagawa Japan"},{"name":"Graduate School of Medicine and Pharmaceutical Sciences, 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